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Published on: January 30, 2014
Epigenetic Adaptation Drives Monocyte Differentiation into Microglia-Like Cells Upon Engraftment into the Central
Jie Liu1, Fengyang Lei1, Bin Yan1,2
1Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA.
Abstract:
The identification of specific markers to distinguish resident microglia from infiltrating monocytes has been a long-standing challenge in neuroscience. Recently, proteins such as P2RY12, TMEM119, and FCRLS have been proposed as microglia-specific and are now widely used to define microglial populations in health and disease. The specificity of these markers was predicated on the assumption that circulating monocytes retain their distinct signatures after entering the central nervous system (CNS). Here, we challenge this paradigm. Using a combination of bone marrow chimeras, single-cell RNA sequencing, ATAC-seq, flow cytometry, and immunohistochemistry, we demonstrate that monocytes engrafting into the CNS acquire de novo expression of these established microglia markers. This phenotypic conversion is driven by profound epigenetic reprogramming, characterized by dynamic changes in chromatin accessibility at key gene loci, including P2ry12, Tmem119, and Aif1 (Iba1), and a shift in transcription factor binding motifs toward a microglial profile. We show this process occurs in the retina following injury and, remarkably, under physiological conditions in the brain and spinal cord, where blood-derived monocytes progressively contribute to the resident myeloid pool. Furthermore, engrafted monocytes downregulate canonical monocyte markers (Ly6C, CD45), eventually becoming indistinguishable from embryonic microglia based on conventional phenotyping. Our findings reveal that infiltrating monocytes undergo extensive epigenetic and transcriptional remodeling to adopt a microglia-like fate, challenging the specificity of current markers and necessitating a re-evaluation of the distinct roles of these two cell populations in CNS pathology.
Insights
Engrafted monocytes in the central nervous system (CNS) can mimic microglia by acquiring specific markers and undergoing epigenetic changes. This challenges the assumption of distinct monocyte and microglia identities in CNS research.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
- Immunology
Background:
- Identifying specific markers for microglia has been a significant challenge in central nervous system (CNS) research.
- Previously proposed microglia-specific markers (P2ry12, TMEM119, Fcrls) relied on the assumption that infiltrating monocytes maintain distinct signatures.
- Emerging evidence suggests infiltrating monocytes can adopt microglia-like traits and a pro-inflammatory profile upon engraftment in the CNS.
Purpose of the Study:
- To investigate whether infiltrating monocytes acquire microglia-specific markers and characteristics in the CNS.
- To explore the epigenetic and transcriptional changes underlying monocyte transformation in the CNS.
- To re-evaluate the specificity of commonly used microglial markers.
Main Methods:
- Bone marrow chimeras were used to track monocyte engraftment.
- Single-cell RNA sequencing and ATAC-seq were employed to analyze transcriptional and epigenetic profiles.
- Flow cytometry and immunohistochemistry were utilized to validate marker expression.
Main Results:
- Engrafted monocytes expressed established microglia markers (P2ry12, TMEM119, Fcrls) and the pan-myeloid marker Iba1.
- Significant alterations in chromatin accessibility and binding motifs indicated a shift towards microglial identity.
- Dynamic regulation of key transcription factors and cell surface markers (CX3CR1, CCR2, Ly6C) was observed in engrafted monocytes.
Conclusions:
- Engrafted monocytes in the retina undergo epigenetic and transcriptional reprogramming, leading to microglia-like signatures.
- The findings challenge the strict distinction between microglia and monocytes in the CNS.
- Future CNS pathology research must consider these monocyte plasticity dynamics to accurately assess microglial and monocyte roles.
